Project Summary Alterations in the coagulation profile after trauma are associated with venous thromboembolic events and subsequent morbidity after traumatic brain injury. Platelet hyperaggregration and microparticle generation play a role in the development of this ongoing coagulopathy. Acid sphingomyelinase activity may contribute to both platelet function and microparticle production. Our preliminary data have demonstrated that traumatic brain injury results in time-dependent changes in platelet aggregation, acid sphingomyelinase activity, ceramide concentration, and subsequent generation of hypercoagulable platelet-derived microparticles.The overall goal of this proposal is to demonstrate that changes in acid sphingomyelinase activity alter platelet function and microparticle generation, leading to hypercoagulability and thromboembolic risk after traumatic brain injury, with the following aims: Aim 1: Elucidate acid sphingomyelinase-dependent factors driving arachidonic acid-induced changes in platelet function following traumatic brain injury. Aim 2: Determine the role of acid sphingomyelinase in modulating platelet-derived microparticle generation and function after stimulation by proinflammatory factors released by traumatic brain injury. Aim 3: Determine how acid sphingomyelinase activity regulates traumatic brain injury-induced platelet-derived microparticle and/or platelet endothelial activation. Successful completion of these aims may lead to novel therapies to reduce posttraumatic thromboembolic events.